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Sirtinol, a Schiff base derived from 2-hydroxy-1-naphthaldehyde, is an inhibitor of sirtuin proteins, a family of deacetylases active in gene regulation and relevant to the study of cancer growth. The formation of copper(II) and zinc(II) complexes of sirtinol is investigated by spectroscopic and structural methods. The molecular structure of this protein inhibitor allows for coordination of first-row transition metals in both tridentate and bidentate fashion. In addition, assays in cultured breast cancer cells reveal that CuII(sirtinol−H)2and previously reported FeIII(sirtinol−H)(NO3)2present enhanced cytotoxicity when compared to the free ligand, and that the ferric complex causes an increase in intracellular oxidative stress. Transition metal coordination in the biological milieu could therefore contribute additional effects to the biological profile of sirtinol. [ABSTRACT FROM AUTHOR]

Cancer is perhaps the fastest growing non-communicable disease in the human population worldwide. Although the molecular mechanism of cancer initiation and progression is known to some extent, however, the majority of pathways responsible for its onset, development and progression are largely unknown. Many members of the nuclear receptors (NRs) superfamily of transcriptional factors have key roles in cancer. Estrogen-related receptor alpha (ERRα) is one of the members of the NR superfamily and studies have linked it with a wide variety of cancers. In endocrine-related cancers such as breast cancer, ERRα regulates a number of target genes directing cell proliferation and growth independent of estrogen receptor alpha (ERα). Knockdown of ERRα in a number of cancer tissues and cell lines significantly reduced tumor growth and malignancy indicating dependence on ERRα activity. The pro-angiogenesis factor vascular endothelial growth factor expression has been shown to be regulated by ERRα and has implications in several types of cancer. The effect of ERRα on cancers seems to be multipronged via regulation of cell cycle regulators, osteopontin, hypoxia inducible factor-1 as well as several energy metabolism genes that are part of glycolysis, TCA cycle, lipogenesis, etc., providing a metabolic twist to cancer. In this article, the action of ERRα on various types of cancers including new developments in this field shall be reviewed. [ABSTRACT FROM PUBLISHER]

Purpose: To evaluate matrix metalloproteinase (MMP) activity and invasion after ionizing radiation (IR) exposure and to determine whether MMP could be epigenetically modulated by histone deacetylase (HDAC) inhibition. Material and methods: Two human breast cancer cell lines (MDA-MB-231 and MCF-7) were cultured in monolayer (2D) and in laminin-rich extracellular matrix (3D). Invasion capability, collagenolytic and gelatinolytic activity, MMP and TIMP protein and mRNA expression and clonogenic survival were analyzed after IR exposure, with and without a HDAC inhibition treatment [1.5 mM valproic acid (VA) or 1 μM trichostatin-A (TSA)]. Results: IR exposure resulted in cell line-dependent stimulation of invasion capacity. In contrast to MCF-7 cells, irradiated MDA-MB-231 showed significantly enhanced mRNA expression ofmmp-1,mmp-3andmmp-13and of their regulatorstimp-1andtimp-2relative to unirradiated controls. This translated into increased collagenolytic and gelatinolytic activity and could be reduced after valproic acid (VA) treatment. Additionally, VA also mitigated IR-enhancedmmpandtimpmRNA expression as well as IR-increased invasion capability. Finally, our data confirm the radiosensitizing effect of VA. Conclusion: These results suggest that IR cell line-dependently induces upregulation of MMP mRNA expression, which appears to be mechanistically linked to a higher invasion capability that is modifiable by HDAC inhibition. [ABSTRACT FROM AUTHOR]

Skeletal metastases occur frequently in patients with breast cancer and are associated with significant morbidity and poor survival. Numerous animal models have been developed to investigate the biology of bone metastases and effective preventative or therapeutic approaches. However, no single animal model recapitulates the complexity of the metastatic process in toto. Therefore, selection of the animal model most appropriate for the question under investigation is crucial for the validity of the experimental outcome. This review provides an overview of the currently available animal models for breast cancer metastasis to bone with an emphasis on innovative xenograft models and imaging technologies. [ABSTRACT FROM PUBLISHER]

The efforts described in this article are aimed at designing organotin polymers that control the growth of breast cancer and to identify structure/property relationships that assist in this goal. The growth of MCF-7 and MDA-MB-231 breast cancer cell lines is inhibited employing a wide range of organotin condensation polymers. The EC50values are primarily dependent on the nature of the Lewis base but the CI50is dependent on both the nature of the Lewis base and Lewis acid. A number of products exhibit CI50values greater than two including a number of organotin polyethers such as those derived from diethylstilbestrol, dienestrol, short-chained dibutyltin polyethers, and hydroquinone derivatives. In most of these cases the MDA-MB-231 cells exhibit greater inhibition compared to the estrogen receptor (ER) MCF-7 cells. The organotin polymers generally exhibit a superior ability to inhibit MCF-7 and MDA-MB-231 breast cell growth compared to the standard cisplatin. [ABSTRACT FROM PUBLISHER]

Previous report of the vast effectiveness of opium derivatives in cancer therapy is leading us to see possible effects of these derivatives on cancer stem cells in order to find new agent for cancer therapy. In this study, cells were stained for CSC markers and sorted by magnetic beads. CSCs exhibit the characteristic CD44+/CD24−/low/ESA+phenotype. Noscapine and papaverine (alkaloids) showed anti-proliferative activity on MCF-7 and MDA-MB-231 cell lines. It was observed that noscapine has more cytotoxic effect on CSC derived from both cell lines compared with their parental cells. Papaverine has more cytotoxic effect on MCF-7 CSCs in comparison with parental cells, while CSCs population of MDA-MB-231 is more resistant to papaverine compared with MDA-MB-231 cells. Noscapine enhances apoptosis in MDA-MB-231 CSCs more than parent cells, while in MCF-7 CSCs the apoptosis is less than parent cells. Our results show that papverine is less active in terms of apoptotic effect on CSCs in both cell lines. Moreover, noscapine arrests MCF-7 and MDA-MB-231 CSCs cell cycle at G2/M phase, while papverine arrests cell cycle at G0/G1 phase. It was suggested different mechanism for apoptotic cytotoxicity. The results of this study show possible specific effects of noscapine on these breast cell lines CSCs. [ABSTRACT FROM AUTHOR]

Phellinus linteus(PL) is a medicinal mushroom due to its several biological properties, including anticancer activity. However, the mechanisms of its anticancer effect remain to be elucidated. We evaluated the inhibitory effects of the ethanolic extract from the PL combined with 5-FU on MDA-MB-231 breast cancer cell line and to determine the mechanism of cell death. Individually, PL extract and 5-FU significantly inhibited the proliferation of MDA-MB-231 cells in a dose-dependent manner. PL extract (30 mg/mL) in combination with 5-FU (10 μg/mL) synergistically inhibited MDA-MB-231 cells by 1.8-fold. PL did not induce apoptosis, as demonstrated by the DNA fragmentation assay, the sub-G1 population, and staining with annexin V-FITC and propidium iodide. The exposure of MDA-MB-231 cells to PL extracts resulted in several confirmed characteristics of autophagy, including the appearance of autophagic vacuoles revealed by monodansylcadaverine staining, the formation of acidic vesicular organelles, autophagosome membrane association of microtubule-associated protein light chain 3 (LC3) characterized by cleavage of LC3 and its punctuate redistribution, and ultrastructural observation of autophagic vacuoles by transmission electron microscopy. We concluded that PL extracts synergized with low doses of 5-FU to inhibit triple-negative breast cancer cell growth and demonstrated that PL extract can induce autophagy-related cell death. [ABSTRACT FROM PUBLISHER]

EGFR tyrosine kinase has been reported mainly in 40-80% of non-small lung cancers, in addition to colon and breast cancers. In this study, we illustrate the synthesis of a highly potent antitumor agent. The synthesized compound 4 was screened at NCI, USA, for antitumor activity against non-small lung cancer, colon cancer and breast cancer cell lines. Results indicated that this compound is more potent antitumor agent compared to erlotinib against all tested cell lines except breast cancer (MDA-MB-468) cell line. In addition, it was tested initially at a single dose concentration of 100 µM over 11 different kinases. At this concentration, 94.45% inhibition of the enzymatic activity of EGFR kinase was observed, while the inhibition in activity was below 55% in all other kinases. Compound 4 was further tested in a 10-dose IC50 mode and showed IC50 value of 0.239 µM for EGFR kinase. In vivo acute toxicity of this compound was also tested. [ABSTRACT FROM AUTHOR]

Lactoferrin (LF) is predominantly found in mammalian secretions with recognized anticancer potential, although the mechanisms involved in such activity are still unclear. Here, the stability, internalization, and cytotoxicity of bovine LF (bLF) and its variants were tested against a panel of breast cancer cells. bLF was found to be very stable under incubation with cells and also able to internalize them, although most of the protein remained in the culture medium. Furthermore, bLF (up to 30 μM) inhibited the growth of breast cancer cells (T-47D, MDA-MB-231, Hs578T, and MCF-7) in a higher extent than in the normal counterpart cell line (MCF-10-2A), thus suggesting its selectivity. Regarding its variants, only the iron-saturated protein showed a higher activity compared with the commercial bLF. bLF growth inhibitory activity was associated with the induction of cell cycle arrest, but not with apoptosis. Moreover, exposure to bLF increased the cells phospho-AMPKα levels and decreased both phospho threonine mammalian target of rapamycin (mTOR) and total mTOR levels, indicating a novel mechanism of action through its ability to induce nutrient/energy-related stress. This study disclosed important findings to better understand the mechanisms underlying the bLF effects on breast cancer cell lines, which could be valuable for novel advances in the cancer research field. [ABSTRACT FROM PUBLISHER]

Purpose: Silver nanoparticles (Ag NP) can generate heat upon exposure to infrared light. The in vitro response of breast cell lines to Ag NP, both with and without nanoparticle-induced heating was evaluated. Materials and methods: Ag NP heat generation, intracellular silver concentration, and cell viability of MDA-MB-231, MCF7, and MCF 10A breast cells with Ag NP alone, or after exposure to 0.79 or 2.94 W/cm2 of 800 nm light were evaluated. Results: The concentration of Ag NP to induce sufficient heat for cell death, upon exposure to 800 nm light, was 5-250 μg/mL. Clonogenics assay indicates a cytotoxic response of MCF7 (45% decrease) and MDA-MB-231 (80% decrease) cells to 10 µg/mL, whereas MCF 10A had a 25% increase. Without Ag NP, MDA-MB-231 cells were more susceptible to hyperthermia, compared to MCF7 and MCF 10A cells. Clonogenics assay of Ag NP-induced photothermal ablation demonstrated that MCF 10A cells have the highest survival fraction. MCF7 cells had more silver in the cytoplasm, MDA-MB-231 cells had more in the nuclei, and MCF 10A cells had equivalent concentrations in the cytoplasm and nuclei. Conclusions: Ag NP are effective photothermal agents. A secondary benefit is the differential response of breast cancer cells to Ag NP-induced hyperthermia, due to increased intracellular silver content, compared to non-tumorigenic breast epithelial cells. [ABSTRACT FROM AUTHOR]

LyP-1 (CGNKRTRGC) is a nine amino acid peptide that shows high specificity for tumor lymphatics. The aim of this study was to develop lipid-based formulations containing the linear form of LyP-1 for lymphatic targeting. Self-microemulsifying drug delivery systems (SMEDDS) were designed for the delivery of linear LyP-1 by itself and as a solid dispersion (SD). Formulations were characterized in terms of physical stability, pH, morphological properties, droplet size distribution and zeta potential. Thermodynamically stable microemulsions were obtained with an average droplet size around 20 nm and zeta potential near neutrality. Cytotoxicity studies of blank and peptide-containing SMEDDS were carried out on Caco-2 cell line. Bioactivity studies of peptide-containing formulations were carried out on MDA-MB-231 breast cancer cell line. It was shown that blank and peptide-containing SMEDDS formulations were not cytotoxic to Caco-2 cell line. However, formulations containing the peptide and peptide SD led to a significant decrease in cell viability on breast cancer cells. It could be concluded that the SMEDDS formulations containing the linear LyP-1 were successfully developed for the lymphatic targeting of solid tumors in vitro. [ABSTRACT FROM AUTHOR]

Targeted uptake of therapeutic nanoparticles in cell- or tissue-specific manner is an attractive technology since they can offer greater efficacy and reduce cytotoxicity on peripheral healthy tissues. In this study, AS1411 (AP), a DNA aptamer specifically binding to nucleolin that is overexpressed on the plasma membrane of breast cancer (BC) cells, was exploited as the targeting ligand of a nanoparticle-based drug delivery system. Vinorelbine (VRL) loaded PLGA-PEG nanoparticles (NP) were formulated by an emulsion/solvent evaporation method, and AP was conjugated to the particle surface using the EDC/NHS technique. The drug-loading efficiency and in vitro drug release studies were measured using HPLC. The resulting AP−NP/VRL formed spherical nanoparticles (<200 nm) with drug loading of about 7% and a stable in vitro drug release profile. Fluorescence microscopy was used to confirm the cellular uptake of the particles and targeted drug delivery. Moreover, cytotoxicity studies were carried out in two different cell lines, MDA-MB-231 BC cells and MCF-10A normal epithelial cells. AP-nucleolin interaction significantly enhanced in vitro cytotoxicity to nucleolin overexpressed cells, as compared with non-targeted nanoparticles, while there was no significant difference in cytotoxicity of the two types of nanoparticles on the nucleolin negative cells. The results further support that AS1411-functionalized nanoparticles are potential carrier candidates for targeted drug delivery towards BC. [ABSTRACT FROM AUTHOR]

The ruthenium(II) complex [Ru([9]aneS3)(phpz)Cl2] (1) ([9]aneS3 = trithiacyclononane, phpz = 5-(2- hydroxyphenyl)-3-[(4-methoxystyryl)pyrazole]) was readily isolated by reacting [Ru([9]aneS3)(DMSO)Cl2] with one equivalent of the ligand phpz. A combination of MS, FT-IR and solution NMR studies (1-D and 2-D) was employed to determine the structural formula of the complex 1, in which phpz coordinates in a monodentate mode to Ru(II) by a simple replacement of the leaving group DMSO of the precursor. The cytotoxic properties of 1 in vitro were investigated by determination of the half-maximal growth inhibition on the human prostate (PC-3) and breast cancer cells (MDA-MB-231). [ABSTRACT FROM AUTHOR]

A new series of N- sec/ tert-butyl 2-arylbenzimidazole derivatives was synthesised in 85-96% yields within 2-3.5 min by condensing ethyl 3-amino-4-butylamino benzoate with various substituted metabisulfite adducts of benzaldehyde under focused microwave irradiation. The benzimidazole analogues were characterised using 1H NMR, 13C NMR, high resolution MS and melting points. Evaluation of antiproliferative activity of the benzimidazole analogues against MCF-7 and MDA-MB-231 revealed several compounds with unexpected selective inhibitions of MDA-MB-231 in micromolar range. All analogues were found inactive towards MCF-7. The most potent inhibition against MDA-MB-231 human breast cancer cell line came from the unsubstituted 2-phenylbenzimidazole 10a. [ABSTRACT FROM AUTHOR]

There is a growing interest in plant polyphenols (including flavanols) that exhibit pleiotropic biological activities such as antiinflammatory, antioxidant, and anticancer effects. Here, we report for the first time the inhibition of MDA-MB-231 breast cancer cell viability and invasiveness by an evening primrose flavanol preparation (EPFP). We observed a decrease in MDA-MB-231 viability of 50% vs. a control after 72 h of incubation with EPFP at a concentration of 58 μM gallic acid equivalents (GAE) and an inhibition of their invasiveness of 65% vs. a control at 75 μM GAE after 48 h of incubation. EPFP caused a 10-fold reduction in matrix metalloproteinase-9 (MMP-9) activity at 100 μM GAE. Furthermore, through modulation of mRNA expression, EPFP reduced the expression levels of the following proteins: antiapoptotic Bcl-2, angiogenic vascular endothelial growth factor (VEGF), and 2 transcription factors (c-Jun, c-Fos). Moreover, analysis by flow cytometry revealed that EPFP induced apoptosis in MDA-MB-231 cells. In conclusion, our data shows that EPFP inhibits cell viability by increasing apoptosis and decreases cell invasiveness by decreasing angiogenesis. [ABSTRACT FROM PUBLISHER]

In this study, we compared MSCs from breast and abdominal tissue in terms of their expression of genes deemed important in the support of breast cancer growth and their effect on gene profile of macrophages after coculture. In addition, we investigated the role of MSCs, alone or in combination with macrophages, on proliferation of breast cancer cell lines. Our results show that MSCs derived from breast and abdominal adipose tissues have a comparable gene expression profile, have similar effect on gene expression of macrophages, and are comparable in supporting breast cancer cell line proliferation. [ABSTRACT FROM AUTHOR]

In London, Ontario, the 13th Annual Joint meeting of the Great Lakes GPCR Retreat and the Club des Récepteurs à Sept Domaines Transmembranaires (known simply as the GPCR Retreat) was held on 17-19 October 2012, organized by Steve Ferguson and Peter Chidiac. This meeting gathered together a core group of investigators from Michigan, Ontario and Québec and has steadily increased its attendance in both the eastern (Europe) and western (USA, Canada) directions. This year's buzz naturally centered around the Nobel Prize in Chemistry, which was won the week before by Brian Kobilka and Robert Lefkowitz for their work on receptor structure and function. Michel Bouvier provided a heartfelt tribute to one of the attendees, Marc Caron, a pioneer in the GPCR field, has made many contributions to the work that led to this year's Nobel Prize. The meeting featured interesting sessions on the physiological roles of GPCRs in the nervous system, circadian biology and cancer, dealing at the cellular and molecular level with GPCR, G protein and effector structure and function, regulation and trafficking - with an overall focus on how to move molecular pharmacology in vivo. [ABSTRACT FROM AUTHOR]

Polyphenols are natural compounds of high structural diversity which translates into a very wide spectrum of biological activities, including chemoprevention. Here we report that a Japanese quince fruit flavanol preparation (JQFFP) caused favorable changes inBax/Bcl-2mRNA ratio, which rendered normal and cancer cells more resistant and more sensitive, respectively, to apoptosis. DU145 human prostate cancer cells were characterized by the most advantageousBax/Bcl-2ratio. The growth and invasiveness of MDA-MB-231 human breast cancer cells were strongly suppressed by JQFFP, which was accompanied with a decrease in MMP-9 activity and stimulation ofTIMP-1expression. Importantly, JQFFP did not decrease normal human prostate PNT1A cell number, whereasBax/Bcl-2ratio decreased which implies increased resistance to apoptosis. In conclusion, JQFFP exhibited a potent antiproliferative effect against cancer cells, inhibited their invasiveness, and decreased expression level of several genes involved in apoptosis, angiogenesis, and metastasis. [ABSTRACT FROM AUTHOR]

Many studies reviewed herein demonstrated the potency of some flavonoids to modulate the activity and/or expression of glutathione S-transferases (GSTs). Because GSTs play a crucial role in the detoxification of xenobiotics, their inhibition or induction may significantly affect metabolism and biological effects of many drugs, industrials, and environmental contaminants. The effect of flavonoids on GSTs strongly depends on flavonoid structure, concentration, period of administration, as well as on GST isoform and origin. Moreover, the results obtained in vitro are often contrary to the vivo results. Based on these facts, the revelation of important flavonoid-drug or flavonoid-pollutant interaction has been complicated. However, it should be borne in mind that ingestion of certain flavonoids in combination with drugs or pollutants (e.g., acetaminophen, simvastatin, cyclophosphamide, cisplatine, polycyclic aromatic hydrocarbons, chlorpyrifos, acrylamide, and isocyanates), which are GST substrates, could have significant pharmacological and toxicological consequences. Although reasonable consumptions of a flavonoids-rich diet (that may lead to GST induction) are mostly beneficial, the uncontrolled intake of high concentrations of certain flavonoids (e.g., quercetin and catechins) in dietary supplements (that may cause GST inhibition) may threaten human health. [ABSTRACT FROM AUTHOR]

Reactivation of tumor suppressor genes (TSGs) involved in carcinogenesis by nontoxic bioactive food component represents a promising strategy for cancer chemoprevention. Recently, curcumin has been demonstrated to inhibit a bacterial DNA methyltransferase (M. Sss I) activity, induce global DNA hypomethylation in leukemia cells, and reactivate several hypermethylation silenced genes in lung and prostate cancer cells. Herein, we demonstrated that curcumin can enhance the mRNA and protein levels of ras-association domain family protein 1A (RASSF1A), 1 hypermethylation-silenced TSG, and decrease its promoter methylation in breast cancer cells. Mechanistic study demonstrated that curcumin can decrease DNA methylation activity of nuclear extract and downregulate the mRNA and protein levels of DNMT1 in MCF-7 cells, which may be associated with curcumin-induced disruption of NF-κB/Sp1 complex bound to the promoter region of DNMT1. Altogether, this study reveals a novel molecular mechanism of curcumin as a chemo-preventive agent for breast cancer through hypomethylation reactivation of RASSF1A. [ABSTRACT FROM PUBLISHER]

Context: Circulating tumor DNA (ctDNA) is a promising biomarker in cancer. Materials and methods: We generated xenograft models of cancer and detected ctDNA in plasma by qRCR targeting human AluJ sequences. Results: Our assay reached single cell sensitivity in vitro and a correlation between ctDNA amount and tumor size was observed in vivo. Treatment with a mitogen activated protein kinase kinase (MEK)-inhibitor (BAY 869766) reduced ctDNA levels. Using this assay, we also confirmed that high levels of cell-free DNA are found in cancer patients compared to healthy individuals. Discussion and conclusion: We show that ctDNA may be useful biomarker for monitoring tumor growth and treatment response. [ABSTRACT FROM AUTHOR]

Thymoquinone (TQ), a drug extracted from the black seeds of Nigella sativa, has been shown to exhibit anti-inflammatory, anti-oxidant, and anti-neoplastic effects in numerous cancer cells. The effects of TQ on cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production in MDA-MB-231, however, remain poorly understood. Western blot analysis and immunofluorescence staining were performed to study the expression levels of inflammation regulatory proteins in MDA-MB-231. PGE2 assay was conducted to explore the TQ-induced production of PGE2. In this study, we investigated the effects of TQ on COX-2 expression and PGE2 production in MDA-MB-231. TQ significantly induced COX-2 expression and increased PGE2 production in a dose-dependent manner, as determined by a Western blot analysis and PGE2 assay. Furthermore, the activation of Akt and p38 kinase, respectively, was up-regulated in TQ treated cells. Inhibition of p38 kinase with SB203580 and PI3kinase (PI3K) with LY294002 abolished TQ-caused COX-2 expression and decreased PGE2 production. These results collectively demonstrate that TQ effectively modulates COX-2 expression and PGE2 production via PI3K and p38 kinase pathways in the human breast cancer cell line MDA-MB-231. [ABSTRACT FROM AUTHOR]

Immunoliposomes (ILs) can be constructed to target the epidermal growth factor receptor (EGFR) to provide efficient intracellular drug delivery in tumor cells. We hypothesized that this approach might be able to overcome drug resistance mechanisms, which remain an important obstacle to better outcomes in cancer therapy. ILs were evaluated in vitro and in vivo against EGFR-overexpressing pairs of human cancer cells (HT-29 and MDA-MB-231) that either lack or feature the multidrug resistance (mdr) phenotype. In multidrug-resistant cell lines, ILs loaded with doxorubicin (DOX) produced 19-216-fold greater cytotoxicity than free DOX, whereas in nonresistant cells, immunoliposomal cytotoxicity of DOX was comparable with that of the free drug. In intracellular distribution studies, free DOX was efficiently pumped out of the multidrug-resistant tumor cells, whereas immunoliposomal DOX leads to 3.5-8 times higher accumulation of DOX in the cytoplasm and 3.5-4.9 times in the nuclei compared with the free drug. Finally, in vivo studies in the MDA-MB-231 Vb100 xenograft model confirmed the ability of anti-EGFR ILs-DOX to efficiently target multidrug-resistant cells and showed impressive antitumor effects, clearly superior to all other treatments. In conclusion, ILs provide efficient and targeted drug delivery to EGFR-overexpressing tumor cells and are capable of completely reversing the multidrug-resistant phenotype of human cancer cells. [ABSTRACT FROM AUTHOR]

Anthracycline antibiotic doxorubicin (DOX) belongs among the most important antineoplastics used in cancer therapy. Unfortunately, its cytostatic effect in therapeutic doses is frequently insufficient; but the use of higher DOX doses is limited by the development of systemic toxicity, especially cardiotoxicity. Therefore, a searching for some possibilities of how to increase DOX efficacy in cancer cells, and minimizing associated toxicities to noncancerous tissues, is in the forefront of scientific research. Many approaches are based on altered DOX metabolism. The classical strategies include an enhancing of DOX uptake by cancer cells and/or an activation of DOX prodrug within cancer cells via liposomal encapsulation or conjugation with antibodies, peptides, or synthetic polymers. The diminishing of DOX deactivation, restriction of DOX efflux from cancer cells, decreased antioxidant defense of cancer cells, changes in cell cycle, or modulation of signaling pathways represent newer approaches in increasing DOX toxicity in tumors. Each way has certain advantages and limitations. The aim of this review was not to collect all reported results, but to bring an overview of various approaches and a summary of their principles. Possible advantages, disadvantages, and further perspectives are discussed and evaluated. [ABSTRACT FROM AUTHOR]

The development of immunotherapies offers significant promise for clinical applications in cancer and infectious diseases. Here the authors describe a novel, integrated approach to immunotherapy that combines novel technologies to discover and target disease-specific peptide/HLA class I complexes. This unique class of markers makes the entire proteome accessible to antibody reagents and offers unsurpassed specificity for targeting cancerous and infected cells. Arm one of the three-armed approach uses an innovative technology for the efficient, direct discovery of new peptide/HLA class I markers. Arm two applies a powerful and inventive strategy to generate T-cell receptor mimics (TCRms), which are antibodies with exquisite binding specificity for peptide/HLA class I markers, and uses TCRms to validate the specific expression of markers on cancerous and infected cells. The third arm uses TCRms to target and kill diseased cells with high sensitivity and specificity. In summary, the combination of two pioneering technologies expands the repertoire of disease-specific markers that can be targeted by therapeutic antibodies and enables a powerful, integrated approach to HLA-based immunotherapy. [ABSTRACT FROM AUTHOR]

Purpose: To examine the molecular mechanism of cellular EGFR activation during hyperthermia treatment. Materials and methods: EGR activities in tumour cells were quantified through the use of a recently developed split-luciferase-based EGFR reporter system which allowed us to monitor EGFR activation in  vitro as well as in  vivo in a non-invasive manner. Results: We found that hyperthermia treatment of MDA-MB231 breast cancer cells resulted in a strong induction of EGFR activity in tissue culture as well as in xenograft tumours. Furthermore, we found that this induction is mediated by the heat shock protein Hsp90. Administration of the specific Hsp90 inhibitor geldanamycin as well as RNAi directed against HSP90 effectively inhibited EGFR activation, suggesting an essential role for Hsp90 in hyperthermia-induced EGFR activation. In addition, cells treated with geldanamycin were sensitised to heat treatment, suggesting that adding Hsp90 inhibitors to hyperthermia regimens might have a beneficial effect for cancer treatment. Conclusions: Our bioluminescent imaging reporter provided a powerful tool to examine hyperthermia-induced EGFR activation in  vitro as well as in  vivo. Hsp90 was found to be a key factor mediating heat-induced EGFR activation in tumour cells. [ABSTRACT FROM AUTHOR]

Gas permeable and biocompatible soft polymers are convenient for biological applications. Using the soft polymer poly(dimethylsiloxane) (PDMS), we established a straightforward technique for in-house production of self-adhesive and optical grade microculture devices. A gas permeable PDMS layer effectively protects against medium evaporation, changes in osmolarity, contamination and drug diffusion. These chip-based devices can be used effectively for long term mammalian cell culture and support a range of bioassays used in pharmacological profiling of anti-cancer drugs. Results obtained on a panel of hematopoietic and solid tumor cell lines during screening of investigative anti-cancer agents corresponded well to those obtained in a conventional cell culture on polystyrene plates. The cumulative correlation analysis of multiple cell lines and anti-cancer drugs showed no adverse effects on cell viability or cell growth retardation during microscale static cell culture. PDMS devices also can be custom modified for many bio-analytical purposes and are interfaced easily with both inverted and upright cell imaging platforms. Moreover, PDMS microculture devices are suitable for extended real time cell imaging. Data from the multicolor, real time analysis of apoptosis on human breast cancer MCF-7 cells provided further evidence that elimination of redundant centrifugation/washing achieved during microscale real time analysis facilitates preservation of fragile apoptotic cells and provides dynamic cellular information at high resolution. Because only small reaction volumes are required, such devices offer reduced use of consumables as well as simplified manipulations during all stages of live cell imaging. [ABSTRACT FROM AUTHOR]

CD44++/CD24−− cells have been associated with breast cancer stem/progenitor cell features. However, the status of this phenotype cells in normal, benign and malignant breast tissues has not been studied, and the clinical correlation of this subpopulation in breast cancer is not fully understood. The present study sought to identify these cells in a series of normal, benign, and malignant breast tissues and explore their correlation to the molecular subtypes of breast carcinoma and conventional pathological features. Double-staining immunohistochemistry (DIHC) of CD44 and CD24 was performed on 30 normal breast tissues, 30 breast fibroadenomas (FA), 60 breast invasive ductal carcinomas (IDC), and 3 breast cancer cell lines (MCF-7, MDA-MB-468, and MDA-MB-231). In the normal breast tissues and FAs, three phenotypes were observed including CD44++/CD24++, CD44++/CD24−−, and CD44−−/CD24−− cells. In the IDCs, CD44−−/CD24++ cells were detected, in addition to the three aforementioned phenotypes. The strong positive rate (++++++, incidence >60%) of CD44++/CD24−− was significantly increased from normal breast tissue, FAs to IDCs (0.0%→→6.7%→→21.7%). However, the CD44++/CD24−− cells didn''t correlate with ages of patients, lymph node metastasis, tumor size, molecular subtypes, and the expression of ER, PR, HER-2, PS2, Bcl-2, nm23. The proportion of CD44++/CD24−− cells in MCF-7, MDA-MB-468, and MDA-MB-231 was about 1, 5, and 80%, respectively. The results indicate that the CD44++/CD24−− cells are transit progenitors and have no association with the molecular subtypes and clinicopathological parameters in the IDCs. [ABSTRACT FROM AUTHOR]

Agonist and antagonist drugs acting on epidermal growth factor receptor (EGFR) signaling are emerging as a new possibility for pharmaceutical study and clinical manipulation of some skin and corneal disorders. EGFR activation appears to be effective in reducing the time of reepithelialization after corneal wound healing, with potential uses in penetrating keratoplasty, refractive surgery, alkali burns, diabetic keratopathy, keratopathy following chemotherapy, cornea transplantation, and dry eye. Most of the studies show therapeutic advantages of human recombinant epidermal growth factor (hrEGF) eye drops without showing adverse effects. In contrast, EGFR inhibition delays epithelial cell proliferation and stratification during corneal regeneration.The aim of this review is to summarize the most seminal discoveries and recent advances so as to clarify the role of the EGFR system in corneal physiology and pharmacology. Epidermal growth factor eye drops could be a first-choice treatment for promoting regeneration in numerous epithelial defects in the medium to long term. [ABSTRACT FROM AUTHOR]

There are conflicting reports with regard to the value of hot peppers and their primary active component compound, capsaicin, as an anticancer agent. We tested extracts from a number of peppers and found them to induce significant growth arrest and apoptosis in human breast and leukemia cancer cell lines in vitro with no significant effect on normal breast epithelial cells. Further, cell growth inhibition and cell death induction were positively correlated with the capsaicin content (based on the Scoville scale) of the peppers, and the hydroxyl radical scavenger thiourea significantly inhibited the activity of pepper extracts, suggesting the involvement of free radicals in mediating the biological activity of the pepper extracts. These results suggest a potential use of pepper extracts as anticancer agents. [ABSTRACT FROM AUTHOR]

Stearic acid (stearate) is an 18-carbon saturated fatty acid that has been shown to inhibit invasion and proliferation and induce apoptosis in various human cell types. The specificity of stearate-induced apoptosis for cancerous versus noncancerous breast cells has not been examined, and the mechanism underlying stearate-induced apoptosis is unknown. Morphological analysis, cell viability, and caspase-3 activity assays demonstrated that stearate activated apoptosis preferentially in cancerous breast cells in a time- and dose-dependent manner. Inhibition of de novo diacylgycerol synthesis or protein kinase C (PKC) blocked stearate-induced caspase-3 activity, indicating the involvement of a novel or classical PKC isozyme. To our knowledge this is the first study showing that stearate induces apoptosis preferentially in breast cancer cells and implicates protein kinase C in the signaling cascade. These results raise the possibility of dietary stearate having a beneficial role in the prevention or treatment of breast cancer. [ABSTRACT FROM AUTHOR]

A series of novel β-lactam containing compounds are described as antiproliferative agents and potential selective modulators of the oestrogen receptor. The purpose of the study is to evaluate the antiproliferative effects of these compounds on human MCF-7 and MDA MB-231 breast cancer cells. The compounds are designed to contain three aryl ring substituents arranged on the heterocyclic azetidin-2-one (β-lactam), thus providing conformationally restrained analogues of the triarylethylene arrangement exemplified in the tamoxifen type structure. The compounds demonstrated potency in antiproliferative assays against MCF-7 human breast cancer cell line at low micromolar to nanomolar concentrations with low cytotoxicity and moderate binding affinity to the oestrogen receptor. The effect of a number of aryl and amine functional group substitutions on the antiproliferative activity of the β-lactam products was explored and a brief computational structure-activity relationship investigation with molecular simulation was investigated. [ABSTRACT FROM AUTHOR]

Organellar and cytosolic pH homeostasis is central to most cellular processes, including vesicular trafficking, post-translational modification/processing of proteins, and receptor-ligand interactions. SLC9A7 (NHE7) was identified as a unique (Na+, K+)/H+ exchanger that dynamically cycles between the trans-Golgi network (TGN), endosomes and the plasma membrane. Here we have used mass spectrometry to explore the affinity-captured interactome of NHE7, leading to the identification of cytoskeletal proteins, cell adhesion molecules, membrane transporters, and signaling molecules. Among these binding proteins, calcium-calmodulin, but not apo-calmodulin, binds to NHE7 and regulates the organellar transporter activity. Vimentin was co-immunoprecipitated with endogenous NHE7 protein in human breast cancer MDA-MB-231 cells. A sizable population of NHE7 relocalized to focal complexes in migrating cells and showed colocalization with vimentin and actin in focal complexes. Among the NHE7-binding proteins identified, CD44, a cell surface glycoprotein receptor for hyaluronate and other ligands, showed regulated interaction with NHE7. Pretreatment of the cells with phorbol ester facilitated the NHE7-CD44 interaction and the lipid raft association of CD44. When lipid rafts were chemically disrupted, the NHE7-CD44 interaction was markedly reduced. These results suggest potential dual roles of NHE7 in intracellular compartments and subdomains of cell-surface membranes. [ABSTRACT FROM AUTHOR]